An anti-CTLA-4 heavy chain-only antibody with enhanced Treg depletion shows excellent preclinical efficacy and safety profile

The value of anti-CTLA-4 antibodies in cancer therapy is well established. However, the broad application of currently available anti-CTLA-4 therapeutic antibodies is hampered by their narrow therapeutic index. It is therefore challenging and attractive to develop the next generation of anti-CTLA-4 therapeutics with improved safety and efficacy. To this end, we generated fully human heavy chain-only antibodies (HCAbs) against CTLA-4. The hIgG1 Fc domain of the top candidate, HCAb 4003-1, was further engineered to enhance its regulatory T (Treg) cell depletion effect and to decrease its half-life, resulting in HCAb 4003-2. We tested these HCAbs in in vitro and in vivo experiments in comparison with ipilimumab and other anti-CTLA4 antibodies. The results show that human HCAb 4003-2 binds human CTLA-4 with high affinity and potently blocks the binding of B7-1 (CD80) and B7-2 (CD86) to CTLA-4. The results also show efficient tumor penetration. HCAb 4003-2 exhibits enhanced antibodydependent cellular cytotoxicity function, lower serum exposure, and more potent antitumor activity than ipilimumab in murine tumor models, which is partly driven by a substantial depletion of intratumoral Tregs. Importantly, the enhanced efficacy combined with the shorter serum half-life and less systemic drug exposure in vivo potentially provides an improved therapeutic window in cynomolgus monkeys and preliminary clinical applications. With its augmented efficacy via Treg depletion and improved safety profile, HCAb 4003-2 is a promising candidate for the development of next generation anti-CTLA-4 therapy

Influence of oxygen concentration on self-compliance RRAM in indium oxide film

This letter investigates various oxygen concentrations in indium oxide films which induce different resistance switching behaviors, including two self-compliance behaviors and a two-step set process. The accumulated oxygen ions produce an oxygen-rich indium oxide film, which can be considered as a variable series resistor after the forming process. Analyses indicate that the lower self-compliance current can be attributed to this larger variable series resistor from the additional oxygen ions. The more significant oxidation reaction decreases the current of the high resistance state. Hence, power consumption can be reduced effectively. ? 2014 IEEE

Ser262 determines the chloride-dependent colour tuning of a new halorhodopsin from Haloquadratum walsbyi

Light is an important environmental signal for all organisms on earth because it is essential for physiological signalling and the regulation of most biological systems. Halophiles found in salt-saturated ponds encode various archaeal rhodopsins and thereby harvest various wavelengths of light either for ion transportation or as sensory mediators. HR (halorhodopsin), one of the microbial rhodopsins, senses yellow light and transports chloride or other halides into the cytoplasm to maintain the osmotic balance during cell growth, and it exists almost ubiquitously in all known halobacteria. To date, only two HRs, isolated from HsHR (Halobacterium salinarum HR) and NpHR (Natronomonas pharaonis HR), have been characterized. In the present study, two new HRs, HmHR (Haloarcula marismortui HR) and HwHR (Haloquadratum walsbyi HR), were functionally overexpressed in Escherichia coli, and the maximum absorbance (λmax) of the purified proteins, the light-driven chloride uptake and the chloride-binding affinity were measured. The results showed them to have similar properties to two HRs reported previously. However, the λmax of HwHR is extremely consistent in a wide range of salt/chloride concentrations, which had not been observed previously. A structural-based sequence alignment identified a single serine residue at 262 in HwHR, which is typically a conserved alanine in all other known HRs. A Ser262 to alanine replacement in HwHR eliminated the chloride-independent colour tuning, whereas an Ala246 to serine mutagenesis in HsHR transformed it to have chloride-independent colour tuning similar to that of HwHR. Thus Ser262 is a key residue for the mechanism of chloride-dependent colour tuning in HwHR

Search for rare decays of Z and Higgs bosons to J/ψ/\psi and a photon in proton-proton collisions at s=\sqrt{s} = 13 TeV

A search is presented for decays of $\mathrm {Z}$ and Higgs bosons to a ${\mathrm {J}/\psi }$ meson and a photon, with the subsequent decay of the ${\mathrm {J}/\psi }$ to $\mathrm {\mu ^+}\mathrm {\mu ^-}$ . The analysis uses data from proton-proton collisions with an integrated luminosity of 35.9 $\,\text {fb}^{-1}$ at $\sqrt{s}=13\,\text {TeV}$ collected with the CMS detector at the LHC. The observed limit on the $\mathrm {Z}\rightarrow {\mathrm {J}/\psi } \gamma$ decay branching fraction, assuming that the ${\mathrm {J}/\psi }$ meson is produced unpolarized, is $1.4\times 10^{-6}$ at 95% confidence level, which corresponds to a rate higher than expected in the standard model by a factor of 15. For extreme-polarization scenarios, the observed limit changes from $-13.6$ to $+8.6\%$ with respect to the unpolarized scenario. The observed upper limit on the branching fraction for $\mathrm {H} \rightarrow {\mathrm {J}/\psi } \gamma$ where the ${\mathrm {J}/\psi }$ meson is assumed to be transversely polarized is $7.6\times 10^{-4}$ , a factor of 260 larger than the standard model prediction. The results for the Higgs boson are combined with previous data from proton-proton collisions at $\sqrt{s}=8\,\text {TeV}$ to produce an observed upper limit on the branching fraction for $\mathrm {H} \rightarrow {\mathrm {J}/\psi } \gamma$ that is a factor of 220 larger than the standard model value.LPHEThis article is licensed under a Creative Commons Attribution 4.0 International Licens

Search for rare decays of Z and Higgs bosons to J/ψ/\psi and a photon in proton-proton collisions at s=\sqrt{s} = 13 TeV

A search is presented for decays of $\mathrm {Z}$ and Higgs bosons to a ${\mathrm {J}/\psi }$ meson and a photon, with the subsequent decay of the ${\mathrm {J}/\psi }$ to $\mathrm {\mu ^+}\mathrm {\mu ^-}$ . The analysis uses data from proton-proton collisions with an integrated luminosity of 35.9 $\,\text {fb}^{-1}$ at $\sqrt{s}=13\,\text {TeV}$ collected with the CMS detector at the LHC. The observed limit on the $\mathrm {Z}\rightarrow {\mathrm {J}/\psi } \gamma$ decay branching fraction, assuming that the ${\mathrm {J}/\psi }$ meson is produced unpolarized, is $1.4\times 10^{-6}$ at 95% confidence level, which corresponds to a rate higher than expected in the standard model by a factor of 15. For extreme-polarization scenarios, the observed limit changes from $-13.6$ to $+8.6\%$ with respect to the unpolarized scenario. The observed upper limit on the branching fraction for $\mathrm {H} \rightarrow {\mathrm {J}/\psi } \gamma$ where the ${\mathrm {J}/\psi }$ meson is assumed to be transversely polarized is $7.6\times 10^{-4}$ , a factor of 260 larger than the standard model prediction. The results for the Higgs boson are combined with previous data from proton-proton collisions at $\sqrt{s}=8\,\text {TeV}$ to produce an observed upper limit on the branching fraction for $\mathrm {H} \rightarrow {\mathrm {J}/\psi } \gamma$ that is a factor of 220 larger than the standard model value